JP4469368B2 - Visceral nerve stimulation for the treatment of obesity - Google Patents

Description

  The present invention relates to neural stimulation for the treatment of medical conditions.

Obesity is prevalent in the United States at a rate of about 20%. US annual medical costs associated with obesity are estimated to exceed $ 200 billion. Obesity is defined by a body mass index (BMI) greater than 30 kg / m ² . The normal value of BMI is 18.5-25 kg / m ² and the BMI of overweight people is 25-30. Obesity is divided into three groups: moderate (Class I), severe (Class II), and very severe (Class III). Patients with a BMI greater than 30 are at risk of serious co-morbidities such as diabetes, heart and kidney disease, dyslipidemia, hypertension, sleep apnea, and orthopedic problems.

  Obesity is caused by an imbalance between food intake and energy consumption that results in a net increase in fat accumulation. This imbalance can be caused by excessive food intake, reduced energy consumption, or both. Appetite and satiety controlling food intake are partly controlled in the brain by the hypothalamus. Energy consumption is also partially controlled in the hypothalamus. The hypothalamus regulates the autonomic nervous system, which branches into sympathetic and parasympathetic nerves. The sympathetic nervous system usually prepares the body for activity by increasing heart rate, blood pressure, and metabolism. The parasympathetic system prepares the body for rest by reducing heart rate, lowering blood pressure, and digestive stimuli. The destruction of the lateral hypothalamus results in reduced hunger, reduced food intake, weight loss, and increased sympathetic activity. In contrast, the destruction of the hypothalamic medial nucleus results in reduced satiety, excessive food intake, weight gain, and decreased sympathetic activity. Visceral nerves carry sympathetic neurons that replenish or innervate the gastrointestinal tract and adrenal gland, and the vagus nerve carries parasympathetic neurons that innervate the digestive system, feeding and weight gain in response to hypothalamic destruction Is involved.

  Experimental and observational evidence indicates that there is a correlation between food intake and sympathetic nervous system activity. Increased sympathetic activity decreases food intake and decreased sympathetic activity increases food intake. Certain peptides (eg, neuropeptide Y, galanin) are known to increase food intake while reducing sympathetic activity. In addition, cholecystokinin, leptin, enterostatin and the like reduce food intake and increase sympathetic nerve activity. In addition, drugs such as nicotine, ephedrine, caffeine, subitramine, dexfenfluramine increase sympathetic activity and reduce food intake.

  Ghrelin is another peptide secreted by the stomach that is involved in hunger. Just before mealtime, a peak in plasma levels occurs and ghrelin levels increase after weight loss. Sympathetic activity can suppress ghrelin secretion. PYY is a hormone that is involved in satiety and is released from the intestines. PYY levels increase after digesting the meal. Sympathetic activity can increase PYY plasma levels.

  Appetite is stimulated by various psychosocial factors, but also by low blood glucose levels. Hypothalamic cells sensitive to glucose levels are thought to be involved in hunger stimulation. Sympathetic activity increases plasma glucose levels. A feeling of satiety is facilitated by a delay in stomach swelling and gastric emptying. Sympathetic activity can reduce gastric and duodenal motility, cause gastric dilatation, and increase pyloric sphincture, resulting in dilation and delayed gastric emptying .

  The sympathetic nervous system is involved in energy expenditure and obesity. Obesity inherited genetically in rodents is characterized by reduced sympathetic activity on adipose tissue and other peripheral organs. Catecholamines and cortisol are released by the sympathetic nervous system but cause a dose-dependent increase in resting energy expenditure. In humans, a negative correlation has been reported between body fat and plasma catecholamine levels. Slimming human subject overeating or reduced eating has a significant effect on energy expenditure and sympathetic nervous system activation. For example, weight loss in obese subjects is associated with a compensatory decrease in energy expenditure, which promotes the recovery of previously lost weight. Drugs that activate the sympathetic nervous system, such as ephedrine, caffeine and nicotine, are known to increase energy expenditure. Smokers are known to have low body fat accumulation and increased energy consumption.

  The sympathetic nervous system also plays an important role in regulating energy substrates for increased consumption, such as fat and carbohydrates. Glycogen and fat metabolism are increased by sympathetic activation and need to support increased energy consumption.

  Various physiological changes are caused by studies on animals that undergo rapid electrical activation of multiple visceral nerves under normal anesthesia. Electrical activation of a single visceral nerve in dogs and cattle causes a frequency-dependent increase in catecholamine, dopamine, and cortisol secretion. Plasma levels can be achieved that cause increased energy consumption. In pigs, cattle, and dogs with adrenalectomy under anesthesia, rapid activation of a single visceral nerve causes an increase in blood glucose and a decrease in liver accumulation of glycogen. In dogs, electrical activation of a single visceral nerve causes increased pyloric sphincter function and reduced duodenal motility. Sympathy and activation of visceral nerves can cause suppression of insulin and leptin hormone secretion.

  The primary treatment for obesity is behavior modification, including reducing food intake and increasing exercise. However, these measures often fail, and pharmacological treatments using such drugs reduce appetite and increase energy expenditure, reinforcing behavioral treatments. Other agents that can cause these effects include dopamine and dopamine analogs, acetylcholine and cholinesterase inhibitors. Pharmacological therapy is usually given orally and causes side effects such as tachycardia, sweating, and hypertension. In addition, tolerance may be manifested in that the response to the drug is reduced even at higher doses.

A more radical form of treatment is surgery. Generally, in these means, the intestinal system is rerouted to reduce the size of the stomach and / or avoid the stomach. Typical measures are gastric bypass surgery and gastric banding. These measures can be very effective in the treatment of obesity, but are highly invasive, necessitating lifestyle changes and can be associated with serious complications.

  Experimental forms of treatment for obesity include electrical stimulation of the stomach (gastric pacing) and electrical stimulation of the vagus nerve (parasympathetic system). In these treatments, a pulse generator is used to electrically stimulate the stomach or vagus nerve through the implanted electrodes. The intent of these treatments is to reduce food intake through the promotion of satiety and / or loss of appetite, and none of these treatments are thought to affect energy expenditure. Cigaina US Pat. No. 5,423,872 describes a putative method for treating eating disorders by electrically pacing the stomach. Wernicke US Pat. No. 5,263,480 discloses a putative method for treating obesity by electrically activating the vagus nerve. None of these treatments increase energy consumption.

  The present invention includes a method for treating obesity or other disorders by electrically activating the sympathetic nervous system with a wireless electrode inductively coupled to a high frequency field. Obesity can be treated by activating the efferent sympathetic nervous system, thereby increasing energy expenditure and reducing food intake. Stimulation has been implanted near various areas of the sympathetic nervous system, such as sympathetic ganglia, visceral nerves (large, small, minimal), or peripheral ganglia (eg, peritoneal cavity, mesentery), or This is accomplished using attached electrodes and a radio frequency pulse generator. Preferably, for the treatment of obesity, electrical activation of the sympathetic nervous system that innervates the digestive system, such as the visceral nerve or celiac ganglion, adrenal gland and abdominal adipose tissue is used. Centripetal stimulation can also be completed to give the central nervous system fullness. Centripetal stimulation can occur secondary to efferent stimulation by a reflex arch. This is preferred because it can accomplish both centripetal and efferent stimulation.

  This method of obesity treatment can reduce food intake by a variety of mechanisms including, for example, increased general sympathetic activation and increased plasma glucose levels associated with activation. A feeling of satiety can be caused by direct effects on the pylorus and duodenum causing reduced peristalsis, gastric dilatation, and / or delayed gastric emptying. In addition, reducing ghrelin secretion and / or increasing PYY secretion can reduce food intake. The method can also cause weight loss by reducing food absorption, possibly due to decreased secretion of digestive enzymes and digestive fluids, and changes in gastrointestinal motility. We have increased fecal excretion, increased PYY concentration (relative to food intake), and decreased ghrelin concentration (relative to food intake) as a result of visceral nerve stimulation according to the stimulation parameters disclosed herein. Is described.

  The obesity treatment method of the present invention can also increase energy expenditure by causing catecholamine, cortisol, and dopamine release from the adrenal glands. This treatment can be titrated with the release of these hormones. Fat and carbohydrate metabolism is also increased by sympathetic activation, but with increased energy consumption. Other hormonal effects induced by this treatment may include a decrease in insulin secretion. Alternatively, the method may be used to normalize catecholamine levels that decrease with weight gain.

  The electrical sympathetic nerve activation for treating obesity is preferably accomplished without causing an increase in mean arterial pressure (MAP). This is done by using an appropriate stimulation pattern with a relatively short signal-conduction time (ie, “conduction period”) followed by an equivalent or longer signal-nonconduction time (ie, “non-conduction period”). Can be achieved. During treatment with activation, MAP may experience sinusoidal variations with an average MAP that is within safe limits. Alternatively, alpha sympathetic receptor blockers such as prazosin can be used to slow down the increase in MAP.

  Electrical sympathetic activation can be titrated at the plasma level of catecholamines achieved during treatment. This allows for monitoring therapy and achieving a safe level of increase in energy consumption. This treatment can also be titrated at plasma ghrelin levels or PYY levels.

  Sympathetic electrical modulation (inhibition or activation) can also be used to treat other eating disorders such as anorexia or bulimia. For example, sympathetic inhibition can be useful for treating anorexia nervosa. Sympathetic electrical modulation may also be used to treat gastrointestinal diseases such as peptic ulcers, esophageal reflux, gastric insufficiency, and irritable bowel disease. For example, stimulation of visceral nerves that innervate the large intestine can reduce the symptoms of irritable bowel syndrome characterized by diarrhea. Since certain pain neurons are carried by the sympathetic nerve, pain can also be treated by electrical neuromodulation of the sympathetic nervous system. This therapy can also be used to treat type II diabetes. These conditions can require varying degrees of inhibition or stimulation.

  In an embodiment, a method for treating a medical condition comprising the step of electrically activating visceral nerves in a mammal according to a stimulation pattern set to result in a net weight loss in the mammal. The stimulation pattern includes stimulation intensity, conduction time, and non-conduction time, and the stimulation pattern is configured such that the ratio of conduction time to non-conduction time is about 0.75 or less. Can be mentioned.

  In some embodiments, the stimulation pattern is set such that the ratio of conduction time to non-conduction time is about 0.5 or less, and in some embodiments is set to about 0.3 or less.

  In some embodiments, the stimulation pattern is set such that the conduction time is about 2 minutes or less. In some embodiments, the stimulation pattern is set such that the conduction time is about 1 minute or less. In some embodiments, the stimulation pattern is set such that the conduction time is about 1 minute or less and the non-conduction time is about 1 minute or more.

  In some embodiments, the stimulation pattern is set such that the conduction time is greater than about 15 seconds. In some embodiments, the stimulation pattern is set such that the conduction time is greater than about 30 seconds.

  In some embodiments, the method further includes the step of varying the stimulus intensity over time, possibly by increasing the stimulus intensity over time daily.

  In some embodiments, the method further includes creating a unidirectional action potential in the visceral nerve. This includes creating an anodic block in the visceral nerve.

  In an embodiment, a method for treating a medical condition, the method comprising electrically activating visceral nerves in a mammal during a first period according to a stimulation pattern, the stimulation pattern comprising: During the second period so that it includes strength and is set to cause a net weight loss in the mammal during the first period and the net weight of the mammal decreases during the second period. Examples include a method including a step of reducing or stopping electrical activation of visceral nerves.

  In some embodiments, the first period is between about 2 weeks and about 15 weeks. In some embodiments, the first period is between about 6 weeks and about 12 weeks. In some embodiments, the second period is between about 1 week and about 6 weeks. In some embodiments, the second period is between about 2 weeks and about 4 weeks.

  In some embodiments, the step of electrically activating the visceral nerve includes sending a stimulation intensity to the visceral nerve that is approximately equivalent to that required to cause skeletal muscle spasm in the mammal. In some embodiments, the intensity of stimulation of visceral nerves is at least about twice that required to produce skeletal muscle spasm in a mammal. In some embodiments, the intensity of stimulation of the visceral nerve is at least about 5 times the intensity of stimulation required to produce skeletal muscle spasm in the mammal. In some embodiments, the intensity of stimulation of the visceral nerve is at least about 8 times the intensity of stimulation required to produce skeletal muscle spasm in the mammal.

  In an embodiment, a method for treating a medical condition comprising the step of electrically activating visceral nerves in a mammal during a first period of less than about 24 hours according to a stimulation pattern, the method comprising: The stimulation pattern includes stimulation intensity and is configured to result in a net weight loss in the mammal and includes stopping electrical activation of visceral nerves for a second period of about 24 hours or less. A method is mentioned.

  Some embodiments further include repeating the electrical activation step and the electrical activation stop step. In some embodiments, the sum of the first period and the second period is equal to about 24 hours.

  In an embodiment, a method for treating a medical condition comprising the step of electrically activating visceral nerves in a mammal according to a stimulation pattern set to result in a net weight loss in the mammal. And the stimulation pattern includes stimulation intensity and frequency, and the frequency is about 15 Hz or more, and includes a method of minimizing skeletal muscle spasm.

  In some embodiments, the frequency is about 20 Hz or higher. In some embodiments, the frequency is about 30 Hz or higher.

  In some embodiments, the stimulation intensity is at least about 5 times the stimulation intensity required to cause skeletal muscle spasm in the mammal. In some embodiments, the stimulation intensity is at least about 10 times the stimulation intensity required to cause skeletal muscle spasm in the mammal, and the frequency is about 20 Hz or more.

  In an embodiment, a method for causing weight loss comprising the step of electrically activating visceral nerves in a mammal according to a stimulation pattern including stimulation intensity and frequency, the stimulation pattern comprising: And methods that are set to reduce the absorption of food from the gastrointestinal tract resulting in increased fecal output in the mammal.

  In some embodiments, the frequency is about 15 Hz or more, about 20 Hz or more, and / or about 30 Hz or more.

  In some embodiments, the stimulation intensity is at least about 5 times the stimulation intensity required to cause skeletal muscle spasm in a mammal.

  In some embodiments, the stimulation intensity is at least about 10 times the stimulation intensity required to cause skeletal muscle spasm in a mammal, and the frequency is about 20 Hz or more.

  In an embodiment, a method for treating a medical condition, the method comprising placing an electrode in the vicinity of the visceral nerve above the diaphragm in a mammal and electrically activating the visceral nerve Is mentioned.

  In some embodiments, the method further includes placing the electrode in contact with a visceral nerve. In some embodiments, the electrode is further helical or has a cuff and further includes attaching the electrode to a visceral nerve.

  In some embodiments, the placement is percutaneous (ie, through the skin). In some embodiments, the placement is in a mammalian blood vessel. In some embodiments, the blood vessel is an azygous vein.

  Some embodiments further include electrically activating the electrode and observing the patient's skeletal muscle spasm and evaluating the placement of the electrode near the visceral nerve.

  In an embodiment, a method for treating a medical condition, the method comprising placing an electrode in a blood vessel of a mammal in the vicinity of the mammalian visceral nerve, and electrically connecting the visceral nerve via the electrode. The method including the process of activating automatically is mentioned. In some embodiments, the blood vessel is an azygous vein. In some embodiments, the electrical activation step follows a stimulation pattern set to provide net weight loss in the mammal.

  In an embodiment, a method for treating a medical condition, the method comprising: electrically activating visceral nerves in a mammal according to a stimulation pattern set to result in net weight loss in the mammal The stimulation pattern includes conduction time, and the conduction time is adjusted based on the blood pressure of the mammal.

  In an embodiment, a method for treating a medical condition, the method comprising: electrically activating visceral nerves in a mammal according to a stimulation pattern set to result in net weight loss in the mammal And the stimulation pattern includes conduction time, and the conduction time is adjusted based on plasma PYY concentration and / or plasma ghrelin concentration in the mammal.

  In an embodiment, a method for treating a medical condition, the method comprising electrically activating visceral nerves in a mammal according to a stimulation pattern, the stimulation pattern including a current amplitude, and the current A method in which the amplitude is adjusted based on skeletal muscle spasm in the mammal can be mentioned.

  In an embodiment, a method for treating a medical condition, the method comprising electrically activating visceral nerves in a mammal according to a stimulation pattern, the stimulation pattern comprising current amplitude and pulse width. And the current amplitude is increased to a first level at which skeletal muscle spasm begins to occur in the mammal, and the method includes the step of keeping the current amplitude at or near the first level until skeletal muscle spasm is reduced or stopped Is mentioned.

  In some embodiments, the method further includes increasing the current amplitude as habituation to skeletal muscle spasm occurs. In some embodiments, the second level at which skeletal muscle spasm begins to recur further includes increasing current amplitude, the second level being above the first level.

  In an embodiment, a method for treating a medical condition, the method comprising electrically activating visceral nerves in a mammal according to a stimulation pattern, the stimulation pattern comprising current amplitude and pulse width. And increasing the pulse width while the current amplitude is increased to a first level at which skeletal muscle spasm begins to occur in the mammal and the current amplitude is substantially at or below the first level. Can be mentioned.

  In an embodiment, a method for treating a medical condition, the method comprising electrically activating visceral nerves in a mammal according to a stimulation pattern, the stimulation pattern including a current amplitude, and the current The amplitude is increased to a first level where skeletal muscle spasm begins to occur in the mammal and includes a method comprising sensing muscle spasm with a sensor in electrical communication with the electrode.

  In some embodiments, the sensor is electrical. In some embodiments, the sensor is mechanical.

  In some embodiments, the method further includes increasing current amplitude as the habituation to skeletal muscle spasm, and implanting the sensor near the abdominal wall to sense abdominal muscle spasm.

  In an embodiment, a device for treating a medical condition, wherein the device is an electrode configured to electrically stimulate a visceral nerve in a mammal, a generation configured to send an electrical signal to the electrode And a sensor in electrical communication with the generator, the sensor is configured to sense muscle spasm, and the device is programmed to electrically stimulate visceral nerves according to a stimulation pattern The stimulation pattern includes current amplitude and pulse width, the device further increases the current amplitude to a first level where skeletal muscle spasm begins to occur, and until the skeletal muscle spasm is reduced or stopped Devices that are programmed to temporarily hold at or near the first level.

  In some embodiments, the device is further programmed to increase the pulse width while keeping the current amplitude at or near the first level. In some embodiments, the device is further programmed to increase current amplitude as habituation to muscle spasm occurs. In some embodiments, the device is further programmed to increase current amplitude to a second level at which skeletal muscle spasm begins to recur, the second level being above the first level.

  In some embodiments, the device is compatible with magnetic resonance imaging. In some embodiments, the device comprises a nanomagnet material.

  In an embodiment, a method for treating a medical condition, wherein the method follows a stimulation pattern set to result in a net weight loss in the mammal without causing a substantial increase in blood pressure in the mammal. And a method comprising a step of electrically activating visceral nerves in the mammal.

  In an embodiment, a method for treating a medical condition, wherein the method does not cause an extension of skeletal muscle spasm in the mammal according to a stimulation pattern set to result in a net weight loss in the mammal, And a method comprising electrically activating visceral nerves in the mammal. As used herein, avoiding prolongation of skeletal muscle spasm (as increasing the intensity of stimulation) is defined as the current amplitude until the animal reaches acclimatization to muscle spasm as soon as the stimulation threshold for muscle spasm is reached in this way. (Or similar parameters such as voltage) are held at or below this level. At that point, the current amplitude can then be increased until muscle spasm recurs at a higher stimulation intensity. The process is then repeated as a “ramp up” protocol with minimal skeletal muscle spasm.

  The invention should be best understood from the accompanying drawings and the following description, wherein like reference characters refer to like parts.

  The human nervous system is a complex network of neurons or neurons found centrally in the brain and spinal cord and peripherally in various nerves of the body. Neurons have cell bodies, dendrites and axons. A nerve is a group of neurons that work for a specific part of the body. A nerve can include hundreds to hundreds of thousands of neurons. Nerves often include both afferent and efferent neurons. Afferent neurons send signals back to the central nervous system, and efferent neurons carry signals to the periphery. A group of neuronal cell bodies in one position is known as a ganglion. Electrical signals are conducted through neurons and nerves. Neurons release neurotransmitters at synapses with other nerves, allowing continuation and modulation of electrical signals. In the periphery, synaptic transmission often occurs in ganglia.

  Neuronal electrical signals are known as action potentials. An action potential occurs when the potential around the cell membrane exceeds a certain threshold. This action potential is then propagated downstream along the neuron. The nerve action potential is complex and represents the sum of the action potentials of the individual neurons within it.

  Neurons can be myelinated and unmyelinated with large and small axons. In general, the rate of action potential conduction increases with myelination and neuronal axon diameter. Therefore, neurons are classified into type A, B and C neurons based on myelination, axon diameter, and axon conduction velocity. In terms of axon diameter and conduction velocity, A is greater than B and B is greater than C.

  The autonomic nervous system is a subsystem of the human nervous system that controls involuntary movements of smooth muscle (blood vessels and digestive system), heart, and glands as shown in FIG. The autonomic nervous system is divided into a sympathetic system and a parasympathetic system. The sympathetic nervous system usually prepares the body for activity by increasing heart rate, increasing blood pressure, and increasing metabolism. The parasympathetic system prepares the body for rest by reducing heart rate, lowering blood pressure, and digestive stimuli.

  The hypothalamus controls the sympathetic nervous system via descending neurons in the anterior horn of the spinal cord as shown in FIG. These neurons synapse with prenodal sympathetic neurons that exit the spinal cord and form white traffic branches. Prenodal neurons may either synapse in the paravertebral ganglion chain or pass through these ganglia and synapse in side branches such as the abdominal cavity or mesentery or in peripheral ganglia . After synaptogenesis at specific ganglia, post-synaptic neurons continue to innervate body organs (heart, intestine, liver, pancreas, etc.) or adipose tissue and peripheral glands and skin. Sympathetic preganglionic neurons can be both small-diameter unmyelinated fibers (C-like) and small-diameter myelinated fibers (B-like). Postnodal neurons are usually unmyelinated C-type neurons.

  Some large sympathetic nerves and ganglia are formed by neurons of the sympathetic nervous system as shown in FIG. The visceral nerve (GSN) passes through the thoracic vertebrae segment 9 or 10 or 11 (T9, T10, or T11) by efferent sympathetic neurons that exit the spinal cord from the thoracic vertebrae 4th or 5th segment (T4 or T5). It is formed. The small visceral (small SN) nerve is formed by prenodal fiber sympathetic efferent fibers from T10 to T12, and the minimal visceral nerve (smallest SN) is formed by fibers from T12. GSNs are usually bilaterally present in animals, including humans, and other visceral nerves have a more irregular pattern and may or may not be unilateral or bilateral. The visceral nerve runs along the anterior-lateral side of the vertebral body, exits the thorax, passes through the diaphragm leg and enters the abdomen. The nerve runs near the aortic vein. Upon entering the abdomen, GSN neurons synapse with postganglionic neurons, primarily within the celiac ganglion. Some GSN neurons pass through the celiac ganglion and synapse in the adrenal medulla. Small and minimal SN neurons synapse with postganglionic neurons of the mesenteric ganglion.

  Postganglionic neurons arising from the celiac ganglion that synapse with the GSN innervate primarily the upper digestive system, including the stomach, pylorus, duodenum, pancreas, and liver. In addition, abdominal blood vessels and adipose tissue are innervated by neurons originating from the celiac ganglion / large visceral nerve. Postganglionic neurons of the mesenteric ganglia supplied by the small and minimal visceral preganglionic neurons provide supply to the lower intestinal tract, colon, rectum, kidneys, bladder, and genitals, and to these organs and tissues The blood vessels to be performed are mainly innervated.

  In the treatment of obesity, a preferred embodiment includes electrical activation of the sympathetic nervous system visceral nerve. Preferably, activation on one side is used, but activation on both sides can also be used. The celiac ganglia, sympathetic chains or ventral spinal nerve roots can also be activated.

  Electrical nerve modulation (nerve activation or inhibition) is accomplished by applying energy signals (pulses) to nerve neurons at specific frequencies (neural stimulation). The energy pulse causes depolarization of neurons within the nerve when it exceeds the activation threshold resulting in an action potential. The applied energy is a function of current (or voltage) amplitude and pulse width or duration. Activation or inhibition can be a function of frequency, with low frequencies on the order of 1-50 Hz resulting in activation and high frequencies above 100 Hz resulting in inhibition. Inhibition can also be achieved by continuous energy delivery resulting in sustained depolarization. Different neuronal types may respond to different frequencies and energies with activation or inhibition.

  Each neuron type (ie, type A, B, or C neuron) has a characteristic pulse amplitude-duration profile (energy pulse signal or stimulus intensity) that leads to activation. Stimulus intensity can be shown as the product of current amplitude and pulse width. Myelinated neurons (types A and B) can be stimulated with a relatively low current amplitude on the order of 0.1-5.0 milliamps and a short pulse width on the order of 50-200 microseconds. Unmyelinated C-type fibers usually require longer pulse widths on the order of 300-1,000 microseconds and higher current amplitudes. Thus, in one embodiment, the stimulus intensity for centrifugal activation will be in the range of about 0.005 to 5.0 mAmp-millisecond).

  The large visceral nerve also contains type A fibers. These fibers can be centripetal and can sense the position or condition of the stomach or duodenum (relaxation against contraction). A fiber stimulation may cause a feeling of fullness by transmitting a signal to the hypothalamus. They can also be involved in reflex arches that affect the condition of the stomach. Since the stimulation parameter that activates the centrifugal B-type fiber should also activate the centripetal A-type fiber, activation of both A and B fibers can be achieved. Activation of type C fibers may cause both afferent and efferent effects and may cause changes in appetite and satiety via central or peripheral nervous system mechanisms.

  Various stimulation patterns ranging from continuous to intermittent can be used. In the case of intermittent stimulation, energy is delivered for a certain time at a specific frequency during the signal-conduction time, as shown in FIG. The signal-on time is followed by a time without energy delivery, referred to as signal-non-conduction time. The ratio of conduction time to non-conduction time is referred to as duty cycle, which can range from about 1% to about 100% in some embodiments. Peripheral nerve stimulation is usually conducted in a nearly continuous, ie 100% duty cycle. However, the optimal duty cycle for visceral nerve stimulation to treat obesity is less than 75% in some embodiments, less than 50% in some embodiments, or even less than 30% in some embodiments. This not only reduces the chances of increased blood pressure or heart rate, but may also alleviate problems associated with muscle spasm. Conduction time can also be important for visceral nerve stimulation in the treatment of obesity. Since the desired effect includes the release of hormones, a conduction time long enough to raise plasma levels is important. Also, the effects on gastrointestinal motility and digestive secretion take time to reach maximum effect. Thus, a conduction time of approximately 15 seconds or in some cases over 30 seconds may be optimal.

  Superimposed on the duty cycle and signal parameters (frequency, conduction time, mAmp, and pulse width) are treatment parameters. Treatment can occur at different intervals or continuously during the day or week. Ongoing treatment can prevent overeating during off-therapeutic times. Intermittent treatment can prevent resistance from developing. Suitable intermittent treatments include, for example, 18 hours conduction and 6 hours non-conduction, 12 hours conduction and 12 hours non-conduction, 3 days conduction and 1 day non-conduction, 3 weeks conduction and 1 week non-conduction, or other A combination of daily or weekly cycles is good. Alternatively, treatment can be performed at a higher rate of intervals, for example, about every 3 hours, for a shorter duration, such as about 2 to 30 minutes. To obtain the desired result, the duration and frequency of the treatment can be tailor made. The duration of the treatment can last from as short as a few minutes to as long as a few hours. Also, visceral nerve activation for treating obesity can be performed at daily intervals that coincide with meal times. The duration of treatment during a mealtime may last 1-3 hours in some embodiments and start just before a meal or about an hour before.

  Eccentric modulation of the GSN can be used to control gastric inflation / deflation and peristalsis. Stomach dilatation or relaxation and reduced peristalsis can cause a feeling of fullness or loss of appetite for the treatment of obesity. These effects are moderate to high intensity (1.0-5.0 milliamp current amplitude and 0.150-1.0 millisecond pulse width) and high frequency (10-20 Hz), centrifugal B Or it can be caused by activating C fibers. Gastric distension can also occur through a reflective arch containing centripetal A fibers. Activation of A fibers can cause loss of appetite or early satiety mediated by the central nervous system. These fibers can be activated with lower region stimulation intensity (0.05-0.150 ms pulse width and 0.1-1.0 mAmp current amplitude) and higher region frequencies. it can. Gastric contractions can also reduce appetite or cause a feeling of fullness. Shrinkage can be caused by activation of C fibers of GSN. Activation of C fibers can also play a role in centrally mediated effects. Activation of these fibers is accomplished at higher stimulation strength (5-10 times that of B and A fibers) and at lower frequencies (10 Hz or less).

  Electrical activation of visceral nerves can also cause muscle spasm of the abdominal and intercostal muscles. Higher frequency stimuli (> 15 Hz) reduce muscle activity, and at higher frequencies (20-30 Hz), muscle spasms are less apparent or are fully acclimated. Short-term muscle contractions are observed during stimulation at 20 or 30 Hz, after which they relax and no further muscle contraction occurs during the rest of the stimulation. This may be due to inhibitory neurons that are activated with temporal weighting.

  The muscle-spasm phenomenon can also be used to help guide the stimulus intensity used for treatment. Once the muscle spasm threshold is reached, at least A fiber activation has occurred. Increasing the current amplitude beyond the threshold may increase the severity of muscle contraction and increase discomfort. Treating at a near threshold for muscle spasms and at a value substantially not above that threshold helps to ensure patient comfort, especially at high frequencies. Once this threshold is reached, the pulse width can be increased 1.5 to 2.5 times longer, thereby increasing the total charge delivered to the nerve without increasing the severity of muscle spasm. By increasing the pulse width at that current, the activation of the B fibers is further ensured. Thus, the current amplitude at a pulse width between 0.100 and 0.150 milliseconds and a frequency of 1 Hz until an osmotic threshold is observed with an electrode placed in close proximity to the nerve (A fiber activation). Can be increased. This will probably occur at a current between 0.25 and 2.5 mAmp, depending on how close the electrode is to the nerve. It should be noted that patient comfort can be achieved with current amplitudes slightly above the muscle spasm threshold, or that effective treatment can be achieved with current amplitudes slightly below muscle spasm, especially with long pulse widths.

  Acclimatization to muscle spasm also occurs so that muscle spasm disappears after a certain period of time. This allows the stimulation intensity to be increased to a height of 10 times the muscle spasm threshold. This can be done without causing discomfort and ensures activation of the C fibers. It was previously thought that high stimulus intensity would result in pain perception, but this does not appear to be observed under experimental conditions. Depending on the nerve or the contact between the electrode and the nerve, the threshold of spasm can vary from patient to patient, so the stimulation intensity of the threshold of muscle spasm can also be used in this case to guide treatment. Once the muscle spasm threshold is determined, the stimulation intensity (current x pulse width) can be increased to 5 or 10 times greater than the threshold. Acclimation occurs by stimulating with a threshold up to 24 hours.

  Increasing the intensity of stimulation after habituation at one level can restore muscle activity, and another period of habituation at a new level may be required. In this way, the stimulus intensity can be increased in steps, allowing habituation in each step until the desired intensity is obtained at 5-10 times the original threshold. This is important because when intermittent treatment frequencies are used, a habituation process to the desired stimulus intensity should occur after each interval when the device is turned off. Preferably, the device is programmed to allow a delay in strength ramp-up from hours to days, allowing habituation to occur at each level. This is not the same as the rapid increase in current amplitude that occurs at the beginning of each conduction time between stimuli. This may be built or programmed directly in the pulse generator, or may be controlled / programmed by the physician to allow for patient variability in acclimation time.

  Alternatively, the device can sense muscle spasm. One way to do this is to implant a pulse generator (IPG) that can be implanted into the muscle surface to be activated. The IPG can then sense spasm electrically or mechanically and increase the stimulus intensity as habituation occurs.

  Centrifugal electrical activation of visceral nerves can cause an increase in blood pressure, eg, mean arterial blood pressure (MAP) above baseline values. This increase in MAP below baseline can be followed by this increase. Since a sustained increase in MAP is undesirable, the stimulation pattern can be designed to prevent an increase in MAP. One strategy would be to have a relatively short signal-conduction time followed by the same or longer signal-nonconduction time. This should be able to bring the MAP back below the baseline. Subsequent signal-conduction time will then raise MAP, but this can start at a lower baseline. In this way, a sinusoidal profile of MAP can be constructed that keeps the average MAP within safe limits during treatment delivery.

  During stimulation, depending on the frequency, MAP may rise at a rate of 0.1-1.0 mmHg / sec, causing a rise more quickly at higher frequencies. An acceptable transient increase in MAP would be about 10-20% of the patient's baseline. If the normal MAP is 90 mmHg, it would be acceptable to increase 9-18 mmHg from baseline during stimulation. Thus, a stimulation conduction time of approximately 9 to 54 seconds is acceptable. The non-conduction time will be longer than the conduction time or longer than 60 seconds. Acclimation can also occur for changes in blood pressure. Thus, after habituation occurs, the conduction time can be allowed to extend beyond 60 seconds.

  In one embodiment, the strategy for treating obesity with visceral nerve stimulation is to stimulate A fibers. The pulse width can be set between 0.05 and 0.15 milliseconds and the current can be increased until the muscle spasm threshold is reached (0.1 to 0.75 mAmp). Other parameters include a 20-50% duty cycle with a frequency of 20-30 Hz and a conduction time of less than 60 seconds. Once acclimatization to MAP rise occurs, conduction time can be extended beyond 60 seconds.

In another embodiment, a strategy for the treatment of obesity by electrical activation of visceral nerves includes stimulating B and A fibers. This strategy involves stimulating the nerve with an intensity 2-3 times the threshold of muscle spasm prior to any habituation. The pulse width can preferably be set from 0.150 ms to 0.250 ms, and the pulse current reaches a desired level above the original muscle spasm threshold (appropriate habituation takes place). Can be increased). Typical parameters are as follows:
Current amplitude: 0.75-2.0 mAmp,
Pulse width: 0.150-0.250 milliseconds,
Frequency: 10-20Hz,
Conduction time <60 seconds,
Non-conduction time> 60 seconds.

  These parameters lead to gastric relaxation and reduced peristalsis, causing an initial feeling of fullness and activation of the dilated receptors in the stomach that reflexively send a satiety signal back to the central nervous system. Since the gastric relaxation effect lasts beyond the period of stimulation, the non-conduction time can be 0.5 to 2.0 times longer than the conduction time. This will reduce the increase in MAP. Once acclimatization to MAP rise occurs, the conduction time can be extended to greater than about 60 seconds, but in some embodiments the duty cycle should remain below about 50%.

In some cases, it may be desirable to activate all types of fibers (A, B and C) of the visceral nerve. This can be done by increasing the stimulation intensity to a level 8-12 times the muscle spasm threshold before habituation. The pulse width can preferably be set to a level of 0.250 milliseconds or more. Typical parameters are as follows:
Current amplitude:> 2.0 mAmp
Pulse width:> 0.250 milliseconds Frequency: 10-20 Hz
Conduction time: <60 seconds Non-conduction time:> 60 seconds.

  Similarly, once acclimatization occurs with this parameter, the duty cycle can be kept between 10% and 50% to reduce the conduction time over a longer period.

It should be noted that the current amplitude varies with the type of electrode used. A spiral electrode in close contact with the nerve will have a lower amplitude than a cylindrical electrode that may be several millimeters away from the nerve. In general, the current amplitude used to cause stimulation is proportional to 1 / (radial distance from the nerve) ² . The pulse width can remain constant or can be increased to compensate for longer distances. The stimulation intensity will be adjusted to activate centripetal / centrifugal B or C fibers depending on the electrode used. Given the variability in contact / distance between nerves and electrodes, using a muscle spasm threshold before habituation can help guide therapy.

  The inventors have found that the weight loss induced by electrical activation of visceral nerves can be optimized by providing intermittent treatment or sections of electrical stimulation and sections without that stimulation. Our data shows that weight loss can be promoted by switching the stimulus off after the stimulation interval. This is in direct contradiction to the notion that termination of treatment will lead to the rebound phenomenon of increased food intake and weight gain. These data also suggest that dynamic or changing stimulus intensity (eg, increasing or decreasing daily) results in more significant weight loss than stimulation at a constant intensity. ing. Based on these findings, two dose strategies are described below.

  These treatment algorithms are derived from studies with dogs. After an appropriate healing time after transplantation (2-6 weeks), the muscle spasm threshold is quantified using a spiral electrode. This threshold may range from about 0.125 mAmp-millisecond to about 0.5 mAmp-millisecond. Stimulus intensity is increased daily over a period of 1-2 weeks, with some or complete between incremental increases until an intensity of 8-10 times the muscle spasm threshold (1.0-5.0 mAmp-sec) is obtained. Allow habituation to muscle spasm. During this period, a rapid decrease in body weight and food intake is observed. After an initial weight loss period, a transient transition period is observed over 1 to 4 weeks, during which some of the lost weight can be recovered. Subsequently, a sustained and gradual decline in body weight and food intake occurs during an extended stimulation phase of 4-8 weeks. After this sustained period of weight loss, stimulation may be terminated, and then again, as in the initial stimulation intensity ramp-up phase, body weight and food intake decrease rapidly. Decrease in body weight and food intake after stimulation can last 1 to 4 weeks, after which the treatment algorithm is repeated to create a treatment cycle that leads to sustained weight loss or intermittent treatment intervals Can do. The duty cycle during this intermittent treatment may be in the range of 20-50% with a stimulation conduction time of 15-60 seconds. This intermittent treatment not only optimizes weight loss, but also extends the battery life of the implanted device.

  In another intermittent therapeutic treatment algorithm embodiment, the therapeutic cycle formation occurs during 24 hours. In this algorithm, the stimulus intensity is maintained at 1-3 times the muscle spasm threshold for 12-18 hours. Alternatively, the stimulation intensity can be increased gradually (eg, every hour) during the first stimulation interval. Stimulation is then terminated for 6-12 hours. Alternatively, the stimulation intensity can be gradually reduced during the second interval until it returns to the muscle spasm threshold level. Because of this persistent or stimulating effect that occurs even after the cessation of stimulation, the risk of overeating and weight gain during non-conduction periods or stimulation intensity decay periods is minimized.

  Alternatively, alpha-sympathetic receptor blockers such as prazosin can be used to slow down the increase in MAP. Alpha-blockers are commonly available antihypertensive drugs. The increase in MAP observed with visceral nerve stimulation is the result of activation of alpha-receptors that mediate arterial contraction. Because the efficacy of this treatment for reducing food intake and energy expenditure is associated with beta-sympathetic receptor activity, it is unlikely that the addition of alpha-blockers will alter the weight loss outcome of treatment.

  In one embodiment, a spiral electrode designed with a platinum iridium ribbon electrode is used. The electrodes surround all or an essential part of the nerve. A balanced charge biphasic pulse is delivered to the electrode, resulting in a bidirectional action potential that activates both efferent and afferent neurons. However, by utilizing an asymmetric waveform between positive and negative phase deflections, it is possible to create a unidirectional action potential that results in an anodic block without accidental centripetal fiber activation. . Thus, while a typical biphasic waveform has equal positive and negative phase deflection (FIG. 11A), the anode block waveform has a short and high positive deflection followed by a long and shallow negative deflection (FIG. 11B). You will have. The amperage x time for each deflection will be the same, so that charge balance will be achieved. Charge balance is a consideration to avoid nerve damage.

  Alternatively, a quadrupolar electrode assembly can be used. A pair of electrodes placed distal to the nerve will be used to produce efferent nerve activation. The proximal second pair will be used to block centripetal A fiber conduction. The blocking electrode pair can have an asymmetric electrode surface area and the cathode surface area is larger than that of the anode (described in Petruska patent 5,755,750) (FIG. 12). Due to the large surface area at the cathode, the charge density will be insufficient to cause activation. The small surface area of the anode will cause hyperpolarization, particularly in the A fibers, thereby blocking centripetal conduction. When an efferent activation pair creates a bidirectional action potential, when the afferent potential is transmitted to the nerve, it sends a signal to four electrodes that are adjusted so that the blocking pair is activated. Can do. Alternatively, blocking pairs can be activated continuously during the treatment period.

  Tripolar electrodes can also be used to perform bilateral activation or unilateral activation of selected fiber sizes. In order to perform bidirectional activation of B fibers and anodic blocking of A fibers, a tripolar electrode with a cathode sandwiched proximally and distally by the anode will be used. Unilateral activation would be accomplished by moving the cathode closer to the proximal electrode and delivering a differential current ratio to the anode.

  Pulse generation for electrical neuromodulation is accomplished using a pulse generator. In the pulse generator, a microprocessor and other standard electrical components can be used. The pulse generator for this embodiment has a frequency in the range of approximately 0.5 Hz to approximately 300 Hz, a pulse width of approximately 10 to approximately 1,000 microseconds, and a constant between approximately 0.1 mA and approximately 20 mA. With current, a pulse, ie an energy signal, can be generated. The pulse generator can produce a raised or ramped increase in current amplitude. A preferred pulse generator can communicate with an external programmer and / or monitor. Passwords, handshakes and parity checks are employed for data integrity. The pulse generator can be battery operated or operated by an external high frequency device. Because the pulse generator, associated components, and battery can be implanted, in some embodiments they are preferably encased in an epoxy-titanium shell.

  An outline of an implantable pulse generator (IPG) is shown in FIG. The component is housed in an epoxy-titanium shell. The battery supplies power to the logic and control unit. The voltage regulator controls the output of the battery. The logic and control unit controls the stimulus output and allows programming of various parameters such as pulse width, amplitude, and frequency. In addition, stimulation patterns and treatment parameters can be programmed in the logic and control unit. A crystal oscillator provides pulses and timing signals for the logic and control unit. An antenna is used to receive communications from external programmers and to check the status of the device. The programmer will allow the physician to program the required increase in stimulation intensity to allow muscle and MAP habituation for a given patient and depending on the treatment frequency. Alternatively, the IPG can be programmed to increase the stimulation intensity at a set rate, such as 0.1 mAmp each time with a pulse width of 0.25 to 0.5 milliseconds. The output section may include a wireless transmitter that is inductively coupled to the wireless electrode and applies energy pulses to the nerve. The reed switch allows manual activation using an external magnet. Devices that are driven by external high frequency devices will limit the components of the pulse generator primarily to the receive coil or antenna. Alternatively, the external pulse generator can be inductively connected directly to the radio electrode implanted near the nerve via electromagnetic waves.

  The IPG is connected to a lead (if used) and an electrode. A lead (if used) is a bundle of electrically conductive wires that are insulated from their surroundings by an electrically non-conductive coating. The lead connects the IPG to the stimulation electrode, which sends an energy pulse to the nerve. A single wire can connect the IPG to the electrode, or a wire bundle can connect the IPG to the electrode. The wire bundle may or may not be knitted. Wire bundles are preferred because they increase reliability and durability. Alternatively, a helical wire assembly can be utilized to improve the resistance to lead bending and tension.

  The electrodes are preferably platinum or platinum-iridium ribbons or rings as shown in FIG. The electrodes can be electrically connected to surrounding tissues and nerves. The electrode can surround a catheter-like lead assembly. The distal electrode can be formed with a rounded cap at the end to create a bullet nose shape. Preferably, this electrode serves as the cathode. This type of lead can include 2 to 4 ring electrodes, with each ring electrode having a width of approximately 1.0 to approximately 10.0 mm, separated by a distance of 2.0 to 5.0 mm. May be. The catheter lead electrode assembly may have an outer diameter of about 0.5 mm to about 1.5 mm to facilitate percutaneous placement using an introducer.

  Alternatively, spiral or cuff electrodes are used as is known to those skilled in the art. A spiral or cuff electrode can prevent the lead from moving away from the nerve. Spiral electrodes may be optimal depending on installation conditions, as opportunities for nerve damage and ischemia may be reduced.

  The generator may be implanted subcutaneously, intraabdominally, or in the thoracic cavity, and / or any suitable location as known to those skilled in the art.

  Alternatively, a wireless system can be employed by providing an electrode inductively coupled to an external high frequency field. Wireless systems will avoid problems such as lead crushing and movement, which are observed in systems that use wires. Allowing easy injection of wireless electrodes in close proximity to visceral nerves and avoiding lead mooring, tunneling and subcutaneous pulse generator implantation will also simplify the implantation procedure Will.

  The wireless electrode would include a coil / capacitor that receives a high frequency signal. The high frequency signal will be generated by a device that creates an electromagnetic field sufficient to supply electricity to the electrodes. It will also provide the desired stimulation parameters (frequency, pulse width, current amplitude, signal, conduction / non-conduction time, etc.). The high frequency signal generator can be externally worn or implanted subcutaneously. The electrode will also comprise a metal component for electrical connection to the tissue or visceral nerve. The metal component can be made of platinum or platinum-iridium. Alternatively, the wireless electrode can have a battery that is charged by a high frequency field, which will then provide stimulation in the absence of the high frequency field.

  Neural bipolar stimulation can be accomplished with multiple electrode assemblies with one electrode acting as a positive node and another electrode acting as a negative node. In this way, nerve activation can be directed primarily in one direction (unilateral), such as efferent, ie, distal from the central nervous system. Alternatively, nerve cuff electrodes can be used. The helical cuff electrode described in Weinberg US Pat. No. 5,251,634 is preferred. The cuff assembly can also include multiple electrodes to direct and cause unilateral nerve activation.

  Unipolar stimulation can also be performed. As used herein, unipolar stimulation means that a single electrode on the lead is used, and the IPG metal shell, or another outer portion of the IPG, is separated from the first electrode as the second electrode. Function. This type of unipolar stimulation may be more suitable for visceral nerves than bipolar stimulation methods, especially when the electrodes are placed percutaneously under fluoroscopic visualization. In percutaneous placement under fluoroscopic observation, the electrodes may not be placed close to the nerve, which may be preferable for bipolar stimulation. In unipolar stimulation, a larger energy field is created to electrically connect the electrode on the lead with the outer portion of the remote IPG, and this generation of large energy field is generated between the single lead electrode and the nerve. Even without close access, nerve activation can be brought about. This allows for successful stimulation with a single electrode placed “normally close” to the nerve, rather than the “close proximity” used for bipolar stimulation. This means that there is a significant gap between them. The size of the acceptable spacing between the electrode and the nerve must depend on the actual energy field created by the operator at the lead electrode to connect to the remote electrode.

  In multiple electrode lead assemblies, some of the electrodes can be used to sense neural activity. This sensed neural activity can serve as a signal to initiate stimulation therapy. For example, afferent action potentials in visceral nerves are created due to the onset of feeding and are used to sense this to activate IPG and initiate stimulation of efferent neurons in visceral nerves can do. Appropriate circuitry and logic for receiving and filtering the sensed signal will be used in the IPG.

  Since visceral nerve branches directly innervate the adrenal medulla, electrical activation of the visceral nerve results in the release of catecholamines (epinephrine and norepinephrine) into the bloodstream. In addition, dopamine and cortisol can be released which also increases energy consumption. Catecholamines can increase energy consumption by about 15% to 20%. In comparison, sabitramine, a drug used to treat obesity, increases energy expenditure by only about 3% to 5%.

  Human resting venous blood levels of norepinephrine and epinephrine are approximately 25 picograms (pg) / milliliter (ml) and 300 pg / ml, respectively, as shown in FIG. Detectable physiological changes, such as increased heart rate, occur at norepinephrine levels of approximately 1,500 pg / ml and epinephrine levels of approximately 50 pg / ml. Norepinephrine venous blood levels can reach as high as 2,000 pg / ml during intense exercise, and epinephrine levels can reach as high as 400-600 pg / ml during intense exercise. Mild exercise results in norepinephrine and epinephrine levels of approximately 500 pg / ml and 100 pg / ml, respectively. During electrical sympathetic activation for the treatment of obesity, it may be desirable to maintain any catecholamine levels with moderate to intense exercise.

  In anesthetized animals, visceral nerve electrical stimulation is frequency dependent in the range of about 1 Hz to about 20 Hz so that catecholamine release / production rates of 0.3-4.0 μg / min can be achieved. It has been shown to increase blood catecholamine levels. These rates are sufficient to increase the plasma concentration of epinephrine from 400 to 600 pg / ml, which then leads to an increase in energy consumption of 10% to 20% as shown in FIG. Can do. During stimulation, the ratio of epinephrine to norepinephrine is 65% to 35%. This ratio can be changed by stimulating at a higher frequency. In some embodiments, this is desirable for changing energy consumption and / or preventing MAP elevation.

  Energy consumption in humans is in the range of approximately 1.5 kcal / min to 2.5 kcal / min. If this energy consumption increases by 15% in a human with an energy consumption of 2.0 kcal / min, the consumption will increase by 0.3 kcal / min. Depending on the treatment parameters, this can lead to an additional consumption of 100 to 250 kcal per day and 36,000 to 91,000 kcal per year. Since 1 pound of fat is 3500 kcal, a weight loss of 10 to 26 pounds is achieved each year.

  Increased energy consumption should be fueled by fat and carbohydrate metabolism. The retronodal branch of the visceral nerve innervates liver and abdominal fat deposition. Activation of visceral nerves can result in fat metabolism and fatty acid release, as well as glycogenolysis and glucose release from the liver. Fat metabolism leading to increased energy consumption can lead to a net decrease in fat accumulation.

  In some embodiments, it may be desirable to titrate obesity treatment with plasma ghrelin levels. In humans, venous blood ghrelin levels range from approximately 250 pg / ml to over 700 pg / ml as shown in FIG. Ghrelin levels increase and decrease throughout the day, usually peaking just before meals. The rapid increase in ghrelin is thought to stimulate appetite and lead to eating. The ghrelin surge can be as high as 1.5 to 2.0 times the baseline level. Total ghrelin production during 24 hours is thought to correlate with the patient's energy status. A diet that results in a state of energy deficiency is accompanied by higher total ghrelin levels in 24 hours. Visceral nerve stimulation has been shown to eliminate or substantially suppress ghrelin surges or spikes. In the canine model, ghrelin levels prior to visceral nerve stimulation showed a sharp increase of approximately 2.0 times baseline levels at midday. After a week of stimulation at 20 Hz with a conduction time of approximately 60 seconds, a non-conduction time of approximately 120 seconds and a peak current intensity of 8 times the threshold of muscle spasm, this midday surge was almost eliminated (FIG. 14). Furthermore, this stimulation increased total ghrelin production at 24 hours, reflecting an energy deficit state (baseline area under the curve = 64.1 × 104, stimulation area under the curve = 104.1 × 104). In the treatment of obesity, visceral nerve activation can be titrated by suppressing the ghrelin surge and reaching the desired energy deficit state for optimal weight loss. A decrease in food intake comparable to an increase in energy consumption (ie, 100 to 250 kcal / day) can result in a total kcal decrease of 200 to 500 per day and a weight loss of 20 to 50 pounds per year.

  In anesthetized animals, electrical activation of visceral nerves has also been shown to reduce insulin secretion. In obesity, insulin levels are often elevated and insulin resistant diabetes (type II) is common. Down-regulation of insulin secretion by visceral nerve activation can help correct insulin-resistant diabetes.

  Implantation of the lead / electrode assembly for activation of the visceral nerve is preferably accomplished percutaneously using an introducer as shown in FIG. The introducer can be a hollow needle-like device placed posteriorly through the skin between the rib para-midline at the T9-T12 level of the thoracic spine. In order to enable electrode placement on both sides of the visceral nerve as needed, posterior placement in a prone patient is preferable. Needle placement can be guided using fluoroscopy, ultrasound, or CT scan. It can be sensed by the introducer in the vicinity of the visceral nerve by activating the nerve by electrically providing energy pulses to the introducer while monitoring for an increase in MAP or muscle spasm. All but the introducer tip can be electrically isolated to concentrate the energy delivered to the introducer tip. The lower the current amplitude used to cause an increase in MAP or muscle spasm, the closer the nerve will be to the tip of the introducer. Preferably, the introducer tip serves as a cathode for stimulation. Alternatively, a stimulation endoscope can be placed in the patient's stomach for electrical stimulation of the stomach. The evoked potential created in the stomach can be sensed in the visceral nerve by the introducer. In order to avoid damage to the spinal nerves, the introducer can sense evoked potentials created by peripheral sensory nerves that are electrically activated. Alternatively, evoked potentials can be created in the lower intercostal or upper abdominal nerve and sensed in the viscera. When the introducer is in close proximity to the nerve, a catheter-type lead electrode assembly will be inserted through the introducer and adjacent to the nerve. Alternatively, a wireless, high frequency battery charged electrode is advanced through the introducer and placed in line with the nerve. In either case, nerve stimulation and monitoring of MAP or muscle spasm elevation can be used to verify electrode placement.

  Once the electrodes are installed, the current amplitude will be increased at a pulse width of 50 to 500 μs and a frequency of 1 Hz until the threshold for muscle spasm is reached. The current amplitude can be set slightly above or slightly below this muscle spasm threshold. After confirming the desired current amplitude, the pulse width can be increased to 2.5 times higher for therapeutic stimulation and the frequency can be increased to 40 Hz. The lead (if used) and IPG will be implanted subcutaneously on the patient's back or flank. The lead is properly secured to avoid detachment. Small visceral nerves and minimal visceral nerves can also be activated to some extent by the placement of leads / electrodes as they are in close proximity to the visceral nerves according to the procedure described above.

Percutaneous placement of the lead electrode assembly can be improved using direct or video assisted visualization. An optical port can be introduced into the introducer. If the nerve is visualized, the channel can allow insertion and localization of the electrode lead assembly. Alternatively, a percutaneous endoscope can be inserted into the thoracic cavity to see the introducer proceeding into the nerve. The parietal pulmonary pleura is relatively transparent and nerves and introducers can be seen running along the vertebral bodies. In prone patients, the lungs are pulled forward by gravity to create an endoscope and observation space. This avoids the need for single lung ventilation. If necessary, one lung can be collapsed to provide space for observation. This is a common and safe means implemented using a bifurcated endotracheal tube. The endoscope can also be placed laterally and the positive pressure of CO ² can be used to push the diaphragm down, thereby creating a space for observing and avoiding lung collapse.

  Alternatively, a stimulation electrode can be placed along the sympathetic ganglion from approximately T4 to T11 of the vertebra. This transplantation can be accomplished by a percutaneous method similar to that described above. This will result in a more universal activation of the sympathetic nervous system, but should also include activation of neurons, including visceral nerves.

  Alternatively, the lead / electrode assembly can be placed intraperitoneally on a portion of the visceral nerve that is present retroperitoneally on the abdominal aorta just prior to synapse formation in the celiac ganglion. Access to the nerve in this area can be accomplished laparoscopically using typical laparoscopic surgical techniques or by employing laparotomy. Cuff electrodes can be used to surround the nerve unilaterally or bilaterally. The lead can be tethered to the diaphragm leg. Cuff or patch electrodes can also be attached to the celiac ganglion unilaterally or bilaterally. Implanting the lead electrode assembly into the thoracic region will cause similar activation of the visceral nerve branch of the sympathetic nervous system.

  Alternative lead / electrode placement is a transvenous approach. Due to the proximity of the visceral nerve to the azygous vein shown in FIG. 10 (particularly the right visceral nerve and the right azygous vein), modulation can be achieved by placing a lead / electrode assembly in this blood vessel. Access to the venous system and the azygous vein can be made via the subclavian vein using standard techniques. The electrode / lead assembly can be mounted on the catheter. A guidewire can be used to place the catheter in the aortic vein. The lead / electrode assembly will include an expandable member such as a stent. An electrode can be attached to the stent and pressed against the vessel wall so that energy delivery can be transferred to the nerve using the balloon expansion of its expandable member. The expandable member allows for fixation of the electrode lead assembly within the blood vessel. The remainder of the lead outside the IPG and vasculature is implanted subcutaneously in a manner similar to a cardiac pacemaker.

  In some embodiments, the device for neural stimulation has the following effects during exposure to a magnetic field: (a) current induction and the resulting thermal effects and potential abnormalities of electronics within the device, And (b) can be shielded or compatible with magnetic resonance imaging (MRI) devices such that the device is less sensitive to the effects of device movement due to Lorentz forces. This type of magnetic shielding can be accomplished, for example, by using a material for the generator and / or electrode that is a nanomagnet or utilizes a carbon composite coating. Such techniques are described in U.S. Patent Nos. 6,506,972 and 6,673,999, and U.S. Patent Application No. 2002/0183796 published Dec. 5, 2002, published Oct. 16, 2003. U.S. Patent Application No. 2003/0195570, and U.S. Patent Application No. 2002/0147470 published Oct. 10, 2002. The entirety of all these cited references is incorporated herein by reference.

  For purposes of overviewing the present invention, certain aspects, advantages, and novel features of the invention have been described herein. It should be understood that not all advantages are achieved in accordance with any of the specific embodiments of the invention. Thus, the present invention seeks to achieve or optimize one or a group of advantages taught herein without necessarily achieving the other advantages taught or suggested herein. May be implemented or implemented.

  While specific aspects and embodiments of the invention have been described, these are given by way of example only and are not intended to limit the scope of the invention. Indeed, the novel methods and systems described herein may be implemented in a variety of forms without departing from the spirit thereof. The appended claims and their equivalents are intended to cover forms or modifications that fall within the scope and spirit of the present invention.

The figure which shows an efferent autonomic nervous system. Anatomical diagram showing the sympathetic nervous system. The front view which shows a visceral nerve and a celiac ganglion. The schematic diagram which shows a typical irritation | stimulation pattern. The schematic diagram which shows a typical pulse generator. FIG. 2 illustrates a typical catheter-type lead and electrode assembly. Graph showing known plasma catecholamine levels in various physiological and pathological conditions. Typical graph showing the effects of visceral nerve stimulation on catecholamine release rate, epinephrine levels, and energy expenditure. Typical graph showing the effects of visceral nerve stimulation on catecholamine release rate, epinephrine levels, and energy expenditure. Typical graph showing the effects of visceral nerve stimulation on catecholamine release rate, epinephrine levels, and energy expenditure. Graph showing known plasma ghrelin levels over a daily cycle for various subjects. FIG. 3 is a cross-sectional view showing a typical instrument installation for implantation of an electrode assembly. The graph which shows an electric signal waveform. The graph which shows an electric signal waveform. The typical side view showing an electrode assembly. The figure which shows the average value of the periodic 7-day body weight of an animal. The figure which shows the plasma ghrelin level before and after visceral nerve stimulation.

Claims (78)

A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
According to the set stimulation pattern so as to provide a weight loss of net in a mammal, the electric electrically activating the generator to set the electrode to electrically stimulate the splanchnic nerve in mammals visceral nerve in mammals The process of sending a signal,
The stimulation pattern includes stimulation intensity, conduction time, and non-conduction time, and the stimulation pattern is set such that a ratio of the conduction time to the non-conduction time is about 0.75 or less.   The method according to claim 1, wherein the stimulation pattern is set so that a ratio of the conduction time to the non-conduction time is about 0.5 or less.   The method according to claim 2, wherein the stimulation pattern is set such that a ratio of the conduction time to the non-conduction time is about 0.3 or less.   The method according to claim 1, wherein the stimulation pattern is set so that the conduction time is about 2 minutes or less.   The method according to claim 4, wherein the stimulation pattern is set so that the conduction time is about 1 minute or less.   The method according to claim 5, wherein the stimulation pattern is set so that the conduction time is about 1 minute or less and the non-conduction time is about 1 minute or more.   The method according to claim 1, wherein the stimulation pattern is set so that the conduction time exceeds about 15 seconds.   The method according to claim 7, wherein the stimulation pattern is set so that the conduction time exceeds about 30 seconds. The method according to claim 1, wherein the control means further performs a step of varying the stimulus intensity with time. The method according to claim 9, wherein the control means further performs the step of increasing the stimulation intensity with time. Control means, method of claim 10, further performing the step of increasing the stimulation intensity daily. Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, method of claim 10, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, method of claim 10, further performing the step of sending an electrical signal from the generator to the electrodes. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Sending an electrical signal from a generator to an electrode configured to electrically stimulate a visceral nerve in a mammal according to a stimulation pattern to electrically activate the visceral nerve during a first period ;
The stimulation pattern includes stimulation intensity and is set to provide a net weight loss in the mammal during the first period, and so that the mammal's net weight decreases during the second period, method for performing the step of sending an electrical signal to the electrodes from a generator, wherein the electrical activation of the splanchnic nerve during said second period is reduced or stopped.   15. The method of claim 14, wherein the first period is between about 2 weeks and about 15 weeks.   The method of claim 15, wherein the first period is between about 6 weeks and about 12 weeks.   15. The method of claim 14, wherein the second period is between about 1 week and about 6 weeks.   The method of claim 17, wherein the second period is between about 2 weeks and about 4 weeks. The method according to claim 14 , wherein the control means further performs a step of varying the stimulation intensity during the first period. Control means, wherein during the first time period, method of claim 19, further performing the step of increasing the stimulation intensity. Control means, in the first period, the method of claim 20, further performing the step of increasing the stimulation intensity daily. Control means, wherein during the first period, according to claim 14 The method according to substantially the same stimulation intensity and stimulus strength required to produce a skeletal muscle spasm in the mammal that sent to the electrodes. Control means, in the first period, the method of claim 14 wherein at least about 2-fold stimulation intensity of the stimulation intensity necessary to produce skeletal muscle spasm in the mammal perform Rukoto sent to the electrode . Control means, in the first period, the method of claim 23 wherein at least about 5-fold stimulation intensity of the stimulation intensity necessary to produce skeletal muscle spasm in the mammal perform Rukoto sent to the electrode . Control means, in the first period, the method of claim 24, wherein at least about 8-fold stimulation intensity of the stimulation intensity necessary to produce skeletal muscle spasm in the mammal perform Rukoto sent to the electrode . Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, The method of claim 14, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, The method of claim 14, further performing the step of sending an electrical signal from the generator to the electrodes. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Sending an electrical signal from a generator to an electrode configured to electrically stimulate a visceral nerve in a mammal according to a stimulation pattern to electrically activate the visceral nerve during a first period of less than about 24 hours. When,
The stimulation pattern includes stimulation intensity and is set to result in net weight loss in the mammal, and the electrical activation of the visceral nerve during the second period within about 24 hours. A method of performing a process of sending an electrical signal to be stopped from a generator to an electrode . Control means, electrically process sends an electrical signal to activation and method of claim 28, further performing the repeating the step of sending an electrical signal to stop the electrical activation.   29. The method of claim 28, wherein the sum of the first period and the second period is equal to about 24 hours. Control means, The method of claim 28, further performing the step of varying the stimulus intensity over time. Control means 32. The method of claim 31, further performing the step of increasing the stimulation intensity with time. Control means 33. The method of claim 32, further performing the step of increasing the stimulation intensity daily. Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, The method of claim 28, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, The method of claim 28, further performing the step of sending an electrical signal from the generator to the electrodes. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
An electrical signal that electrically activates the visceral nerve from the generator to an electrode set to electrically stimulate the visceral nerve in the mammal according to a stimulation pattern set to result in a net weight loss in the mammal. perform the step of sending,
The method wherein the stimulation pattern includes stimulation intensity and frequency, and the frequency is about 15 Hz or more to minimize skeletal muscle spasm.   38. The method of claim 36, wherein the frequency is greater than about 20 Hz.   38. The method of claim 37, wherein the frequency is about 30 Hz or greater.   37. The method of claim 36, wherein the stimulation intensity is at least about 5 times the stimulation intensity required to cause skeletal muscle spasm in the mammal.   40. The method of claim 39, wherein the stimulus intensity is at least about 10 times the stimulus intensity required to cause skeletal muscle spasm in the mammal and the frequency is greater than or equal to about 20 Hz. Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, The method of claim 36, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, The method of claim 36, further performing the step of sending an electrical signal from the generator to the electrodes. A method of controlling a device for causing weight loss, comprising:
The control means
Sending an electrical signal from a generator to an electrode configured to electrically stimulate a visceral nerve in a mammal according to a stimulation pattern including a stimulation intensity and frequency, and electrically stimulating the visceral nerve A method wherein the pattern is set to reduce the absorption of food from the gastrointestinal tract resulting in an increase in fecal output in the mammal.   44. The method of claim 43, wherein the frequency is about 15 Hz or greater.   45. The method of claim 44, wherein the frequency is about 20 Hz or greater.   46. The method of claim 45, wherein the frequency is about 30 Hz or greater.   44. The method of claim 43, wherein the stimulation intensity is at least about 5 times the stimulation intensity required to cause skeletal muscle spasm in the mammal.   48. The method of claim 47, wherein the stimulation intensity is at least about 10 times the stimulation intensity required to cause skeletal muscle spasm in the mammal and the frequency is about 20 Hz or more. A method for treating a condition controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
How to do the electrodes provided in the vicinity of the splanchnic nerve above the diaphragm in a mammal, the step of sending an electric signal for electrically activating the splanchnic nerve from the generator. 50. The method of claim 49 , wherein the control means sends an electrical signal to the electrode placed in contact with the visceral nerve. The electrode is helical or has a cuff;
52. The method of claim 49 , wherein the control means sends an electrical signal to the electrode attached to the visceral nerve. 50. The method of claim 49 , wherein the control means sends an electrical signal to the electrode placed percutaneously. 50. The method of claim 49 , wherein the control means sends an electrical signal to the electrode placed in the mammalian blood vessel.   54. The method of claim 53, wherein the blood vessel is an aortic vein. Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, The method of claim 49, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, The method of claim 49, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, the step of electrically activating the electrode, and on the basis of the skeletal muscle spasm in patients sensed by the sensor, the further a step of evaluating the installation of the electrodes in the vicinity of visceral nerve claim 49 The method described. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
A method of performing a step of sending an electrical signal for electrically activating the visceral nerve from a generator to an electrode installed in a blood vessel of the mammal in the vicinity of the visceral nerve of the mammal.   55. The method of claim 54, wherein the blood vessel is an azygous vein. 55. The method of claim 54, wherein sending the electrically activating electrical signal follows a stimulation pattern set to provide a net weight loss in the mammal. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
According to the set stimulation pattern so as to provide a weight loss of net in a mammal, the electric electrically activating the generator to set the electrode to electrically stimulate the splanchnic nerve in mammals visceral nerve in mammals The process of sending a signal,
The stimulation pattern includes a conduction time, and the conduction time is adjusted by control means based on the blood pressure of the mammal. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Electrically activate the visceral nerve in the mammal from the generator to the electrode set to electrically stimulate the visceral nerve in the mammal according to a stimulation pattern set to result in a net weight loss in the mammal Perform the process of sending electrical signals,
The stimulation pattern includes conduction time, and the conduction time is adjusted by a control means based on plasma PYY concentration in the mammal. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Electrically activate the visceral nerve in the mammal from the generator to the electrode set to electrically stimulate the visceral nerve in the mammal according to a stimulation pattern set to result in a net weight loss in the mammal Perform the process of sending electrical signals,
The stimulation pattern includes conduction time, and the conduction time is adjusted by a control means based on plasma ghrelin concentration in the mammal. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
According to a stimulation pattern, performing an electrical signal from a generator to an electrode set to electrically stimulate a visceral nerve in a mammal to electrically activate the visceral nerve in the mammal ;
The stimulation pattern includes current amplitude;
The method wherein the current amplitude is adjusted by control means based on skeletal muscle spasm in the mammal sensed by a sensor . A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Sending an electrical signal from a generator to an electrode configured to electrically stimulate a visceral nerve in a mammal according to a stimulation pattern to electrically activate the visceral nerve in the mammal ;
The stimulation pattern includes current amplitude and pulse width;
The current amplitude is increased to a first level where skeletal muscle spasm begins to occur in the mammal;
Until the skeletal muscle spasm is sensed by the sensor is reduced or stopped, the method of performing the step of keeping the current amplitude near the first level or said first level. Control means, as habituation to the skeletal muscle spasm sensed by the sensor occurs, The method of claim 65, further performing the step of further increasing the current amplitude. Control means, to a second level of rank muscle spasm begins to recur, further performs the step of further increasing the current amplitude The method of claim 65, wherein said second level above the first level. Control means, in accordance with the stimulation pattern to create a unidirectional action potentials in the splanchnic nerve, The method of claim 65, further performing the step of sending an electrical signal from the generator to the electrodes. Control means, in accordance with the stimulation pattern to create the anodic blocks the splanchnic nerve, The method of claim 65, further performing the step of sending an electrical signal from the generator to the electrodes. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Sending an electrical signal from a generator to electrically activate a visceral nerve to an electrode configured to electrically stimulate the visceral nerve in a mammal according to a stimulation pattern ;
The stimulation pattern includes current amplitude and pulse width;
The current amplitude is increased to a first level where skeletal muscle spasm begins to occur in the mammal;
A method of performing the step of increasing the pulse width while maintaining the current amplitude substantially at the first level or below the first level. A device for treating a medical condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
Electrodes configured to electrically stimulate visceral nerves in mammals,
A generator configured to send an electrical signal to the electrode, and a sensor in electrical communication with the generator, the sensor configured to sense muscle spasm,
The device is programmed to electrically stimulate the visceral nerve according to a stimulation pattern, the stimulation pattern including a current amplitude and a pulse width;
The device further increases the current amplitude to a first level where skeletal muscle spasm begins to occur and temporarily reduces the current amplitude to or near the first level until the skeletal muscle spasm is reduced or stopped. A device that is programmed to hold on to it. 72. The device of claim 71 , wherein the device is further programmed to increase the pulse width while maintaining the current amplitude at or near the first level. 72. The device of claim 71 , wherein the device is further programmed to increase the current amplitude as habituation to the muscle spasm occurs. 72. The device of claim 71 , wherein the device is further programmed to increase the current amplitude to a second level at which skeletal muscle spasm begins to recur, the second level being greater than the first level. 72. The device of claim 71 , wherein the device is compatible with magnetic resonance imaging. 76. The device of claim 75 , wherein the device comprises a nanomagnet material. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
Avoid substantial increases in blood pressure in mammals, from generators to electrodes set to electrically stimulate visceral nerves in mammals according to stimulation patterns set to result in net weight loss in mammals while, a method of performing the step of sending an electric signal for electrically activating the splanchnic nerve in said mammal. A method of controlling a device for treating a condition that is obesity, eating disorders, gastrointestinal tract disease, or type II diabetes ,
The control means
According to the stimulation pattern set to result in net weight loss in the mammal, from the generator to the electrode set to electrically stimulate the visceral nerve in the mammal, while avoiding prolonged skeletal muscle spasm in the mammal the method of performing the step of sending an electric signal for electrically activating the splanchnic nerve in said mammal.

Images